3.7 Mutation and human disease and 3.1.5 Organisation of the genome Flashcards
1
Q
What are the types of spontaneous mutation?
A
Changes to the chemical properties of nucleic acids
Problems that arise during replication or cell division
2
Q
What are the types of induced mutation?
A
Effects of radiation
Effects of chemicals
3
Q
What are mutations?
A
Changes in DNA/in the structure of a gene, ranging from single base changes to alterations in whole chromosomes or chromosome sets.
4
Q
What type of mutation is deamination?
A
Spontaneous
5
Q
What happens during deamination?
A
An amino group is removed
6
Q
What is the bases are usually involved in deamination?
A
Cytosine bases are usually deaminated to form uracil bases.
7
Q
What are the consequences of deamination?
A
Uracil bases are complementary to adenine bases, not guanine, so the base sequence will be changed on the mutated strand and the new strand synthesised from that template.
8
Q
What is depurination?
A
This is the removal of a purine base (guanine or adenine) from a nucleotide, leaving only a nucleoside (so has an exposed OH group)
9
Q
What are the consequences of depurination?
A
On the DNA strands synthesised from the template which had the based removed/underwent depurination, an entire base will be removed, resulting in a frame-shift deletion mutation.
10
Q
How can errors occur during replication?
A
Bases can be incorrectly paired during synthesis an then bound into the strand, resulting in one out of four granddaughter molecules containing the mutation
11
Q
What type of mutation are replication errors?
A
Spontaneous
12
Q
What can occur if the polymerase enzyme slips during DNA replication?
A
Repeat units can be extended (only really occurs at tandem repeats) as the polymerase enzyme is incorrectly positioned, so binds more repeating nucleotides that necessary.
- The number of tandem repeats present in Huntington’s disease dictates severity of symptoms
13
Q
What type of mutation is polymerase slippage during replication?
A
Spontaneous
14
Q
What type of mutations arise from radiation?
A
Induced
15
Q
Which base does UV exposure affect?
A
Thymine
16
Q
What happens to adjacent thymine bases when exposed to UV light?
A
They can undergo dimerization (two molecules react to form one). Two thymine molecules become covalently linked which causes a kink in the DNA and affects replication.
17
Q
- What clinical relevance is related to UV light exposure/REM (unit of effective dose of ionising radiation absorbed by the body)?
A
Melanoma - mutations in repair enzymes xeroderma pigmentosum (XP) increase susceptibility to melanoma, which is a skin cancer affecting the pigment cells within skin/melanocytes
18
Q
What systems limit damage to DNA?
A
Repair systems
19
Q
What is a method of direct repair?
A
The use of alkylating agents - incorrect methyl or ethyl groups present on a nucleotide can be removed by repair enzymes, with the group being transferred to the enzyme from the base.
20
Q
What is excision repair?
A
This is where single bases - for example, a cytosine that has been deaminated to make a uracil base - can be removed or ‘excised’ through the action of DNA glycosylases.
The exposed strand can then attract correct complementary bases to re-synthesise the gap and reform the double strand.
21
Q
What is a mismatch repair?
A
This is where larger regions of DNA can be excised from a faulty DNA strand (i.e. if thymine dimerization has occurred), then allowing for re-synthesis to occur.
22
Q
What is nonhomologous end-joining?
A
This is where a double stranded break with no complementary or homologous template is directly ligated to reattach the two double strands of DNA.
23
Q
Are repair machineries specific?
A
Yes, to the type of damage
24
Q
What is homologous recombination?
A
This is where a double stranded break results in ‘sticky ends’ or templates which will combine the two strands
25
What happens if repair processes/proteins become mutated/their genes become compromised?
This elevates the patient's susceptibility to cancer
26
* Give an example of a disease that can occur if single nucleotide repair genes (XP) become compromised.
Xeroderma pigmentosa - this results in a decreased ability to repair skin after exposure to UV light (often thymine dimerization), resulting in severe sunburn after minimal exposure and increased risk of melanoma.
27
* Give an example of a disease that can occur if DNA mismatch repair genes (MLH1/MSH2) become compromised.
Hereditary nonpolyposis colorectal cancer autosomal dominant (syndrome which results in a very high risk of developing colon cancers, including endometrial/uterine cancers).
28
* Give an example of a disease that can occur if double strand break repair protein genes (BRCA1/2) become compromised?
Familial breast and ovarian cancer - the risk of these two cancers developing increases.
29
What is a missense mutation?
This is a mutation that results in a codon being recognised by a different tRNA molecule, therefore introducing a potentially different amino acid to the polypeptide chain being formed.
30
What is a silent mutation?
This is a missense mutation but where the change in tRNA molecule that recognises the mutated codon still carries the same amino acid as originally being coded for, and this is allowed through DNA being a degenerate code (several codons have the same meaning).
31
What is a nonsense mutation?
This is where the mutation of a codon introduces a premature stop codon in the mRNA, resulting in the early dissociation of the ribosome and production of an ineffective or shortened protein, which may limit function or display slightly altered regulation.
32
What is another name for a silent mutation?
Synonymous substitution
33
What is another name for a missense or nonsense mutation?
Non-synonymous substitution
34
What is the effect on a protein of a deletion of nucleotides that is a multiple of three?
Entire codons - and therefore amino acids - will be removed, not substituted, which could result in a reduction of stability for the protein or a reduction/loss of function.
35
What type of mutation is a deletion that removes a number of nucleotides that isn't a multiple of 3?
Frame shift - this can result in premature termination, gain, or loss of function of the protein.
36
What type of mutation is a large deletion?
Partial or whole gene deletion - this can result in loss of function or loss of expression entirely.
37
What effect does a multiple of three insertion have on protein function?
Can be in or out of frame, but can affect stability and function of protein due to presence of extra amino acid(s)
38
What type of mutation is an insertion that is not a multiple of three?
A frame shift mutation, which could result in premature termination or loss/gain of function.
39
What type of mutation is a large insertion?
Partial or whole gene duplication, which can affect function of the protein or dosage/amount present within the cell.
40
What type of mutation is a trinucleotide insertion?
This is a dynamic mutation, and can result in altered function and stability of the protein.
41
What is trinucleotide sequence expansion/anticipation?
This is where repeats of a certain nucleotide or pattern are expanded, which can result in disease in some cases, if they exceed certain numbers (seen in Huntington's disease).
42
What are single nucleotide polymorphisms (SNP)?
This is where a single nucleotide (one in every 300) is polymorphic/can take different forms, i.e. is different between two chromosomes within the same organism/differs between two organisms of the same species.
Usually have no significant phenotype, as unfavourable polymorphisms would be selected against/favourable ones selected for.
43
How can single nucleotide polymorphisms (SNPs) be used?
They are used in gene linkage analysis (there is an SNP database), often lots in even relatively short chromosome regions and can be easily checked.
Often used in genetic testing and comparison between genes and how they're linked.
44
What is the effect of a gain of function mutation on the protein product?
Novel or excess protein products seen, can be beneficial.
45
What is the effect of a loss of function mutation on the protein product?
Reduced or eliminated protein product.
46
What is the effect of dominant negative mutations on the protein product?
This is where the protein produced by the gene on one chromosome is abnormal and interacts/interferes with the normal protein product produced by the unmutated gene on the other homologous chromosome.
47
What are different forms of a gene called?
Alleles, result in different phenotypes.
48
What is the term for when both alleles are the same?
Homozygous (can be dominant or recessive)
49
What is the term for when the alleles differ?
Heterozygous
50
* What are the alleles present in Mendel's round and wrinkly peas?
Round (RR, Rr) peas contain either two (RR, homozygous) or one (Rr, heterozygous) copies of a functional SBE1 gene, which codes for an enzyme that allows sucrose to be converted into starch - this results in rounded peas
Wrinkled (rr) peas are homozygous recessive, containing two copies of non-functional SBE1 genes, meaning that sucrose cannot be converted into starch and resulting in a high sucrose and low water pea with wrinkled skin. Mutant SBE1 contains an frame-shift insertion, causing the gene to become non-functional.
51
How many copies of a dominant allele are required to confer the phenotype?
Just one
52
How many copies of a recessive allele are required to confer the phenotype?
Two copies
53
* What dominant mutation causes postaxial polydactyly (extra digit on the lateral side of the limb, i.e. extra little toe)?
This is a mutation in the GLI3 gene, which codes for a transcription repressor protein, down-regulating the expression of several genes. If a mutation occurs in this gene (the mutation is dominant, G, and normal genotype recessive, g) then expression levels of these target proteins are higher than they should be, resulting in the formation of the extra digit.
54
* What recessive mutation causes oculocutaneous albinism?
If a child inherits two mutated tyrosinase genes from their parents, they will express this phenotype - parents can be carriers but not show the disease/in heterozygotes the effect of the recessive t allele is masked.
Phenotypes of this genetic mutation are a lack of pigment in skin, hair and eyes, resulting in very pale appearances all round. Eyesight can also be seriously affected.
55
What is a phenotype?
This is the observable characteristic of an organism
56
What is a genotype?
This is a description of the genetic makeup of an organism
57
What determines phenotypes?
Both the genotype AND the environment
| i.e. human body size is influenced about equally by the genome and the environment
58
* How can the effects of environment on phenotype be observed?
Twin studies
59
What is trisomy?
This is where three copies of a chromosome are inherited by offspring due to nondisjunction during meiosis
60
What is monosomy?
This is where only one copy of a chromosome is inherited by offspring due to nondisjunction during meiosis
61
When does nondisjunction occur during meiosis?
Either during meiosis I (homologous pair both in one cell after first division) or during meiosis II (sister chromatids fail to separate during meiosis II, so end up in the same gametocyte)
62
* What syndromes arise as a result of trisomy?
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Down syndrome (trisomy of chromosome 21)
Edward's syndrome (trisomy of chromosome 18)
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63
What is a chromosomal translocation?
This is where sections of DNA can be transferred between non homologous chromosomes - translocations can be balanced or unbalanced depending on the other chromosomes.
64
* What consequence can chromosomal translocation have for offspring?
If one parent has a translocation affecting two nonhomologous chromosomes, one these can be inherited by the offspring with the other type of chromosome involved in the translocation mutation being normal/having two unmutated copies present in the offspring. This means that a region of DNA is missing from the offspring's genome due to the inheritance of only one chromosome with the translocation mutation, which can cause defects such as congenital heart deformities.
65
What is recombination?
This is the reciprocal exchange of genetic information between chromatids on homologous chromosome pairs whilst they are aligned during meiosis I.
66
What controls frequency of recombination?
The distance between two loci
67
What are the two genomes in eukaryotes?
The nuclear and the mitochondrial genomes
68
What is the structure and inheritance of the mitochondrial genome?
More like prokaryotic genetic information - the chromosomes are circular. Inherited from the mother.
69
What is the structure and inheritance of the nuclear genome?
Classic eukaryotic genetic information - long, linear chromosomes with associated proteins. Inheritance is both maternal and paternal.
70
What does the majority of the mitochondrial genome do?
Code for proteins (~66%)
71
What is the majority of the nuclear genome?
Transposon-based repeats (~45%) or other sequences (~44%) - only ~1.1% codes for proteins.
72
How many genes does the mitochondrial genome contain?
37 -> 24 encode non-coding RNAs and only 13 code for polypeptides
73
Does the mitochondrial genome contain introns?
No
74
Where does the majority of the mitochondrial proteome arise from?
The nuclear genome, peptides are imported to the mitochondria.
75
What are the different strands on the mitochondrial chromosome?
Heavy and light strands
76
Why is one strand of the mitochondrial chromosome known as the heavy strand?
Because it is physically heavier. It has a higher proportion of guanine and adenine bases (both purines, with a higher molecular mass).
77
Which genome has a higher number of protein-coding genes?
Nuclear (~21000 to 13)
78
Which genome has a higher number of genes that code for functional RNA molecules?
Nuclear (unknown, >6000 to 24)
79
Which genome has a higher gene density?
Mitochondrial (1 gene per 0.45 kilobases, whereas nuclear has 1 gene per 120 kilobases, although this number has high uncertainty)
80
What are the differences in transcription between the two genomes?
In the nuclear genome, genes are usually independently transcribed, whereas in the mitochondrial genome, multigenic transcripts (multiple genes) are produced from both the heavy and the light strands.
81
Introns are found in which genome?
Nuclear
82
What is the percentage of protein-coding DNA for each genome?
~1.1% for nuclear
| ~66% for mitochondrial
83
How much of the human genome (both nuclear and mitochondrial genomes combined) contains repeat regions?
40%
84
What are transposons?
Mobile DNA elements
85
What are retrotransposons?
DNA sequences that have an RNA intermediate that can then be reverse transcribed into DNA. Causes an amplification of the repeat in the DNA.
86
What are DNA transposons?
Regions of DNA that can be cut out of the sequence and pasted elsewhere.
87
What are tandem repeat regions?
Where one or two nucleotides in a pattern are repeated directly adjacent to each other within the DNA sequence (*tandem repeats of amino acids can also be seen within proteins/primary protein structure, such as armadillo proteins)
88
What is satellite DNA?
This term generally described larger repeats of sequence in tandem/adjacent to each other. Very large arrays, seen in centromeric regions and interspersed throughout the chromosome.
89
What are VNTRs/microsatellite DNAs?
Variable number tandem repeats - a location within the chromosome where a short sequence has a series of repeats in tandem with one another.
Can be non-coding or seen in exons,
90
What is minisatellite DNA?
Repeat units of around 40-50 nucleotides.
91
What is microsatellite DNA?
Repeat units of 1, 2 or 4 nucleotides.
92
* What is a point of clinical relevance related to VNTRs?
Huntington's disease - the number of VNTRs present in the genome has been seen to dictate the relative time of onset and severity of the disease.
93
What is the importance of polymorphism in repeat regions/VNTRs?
For example, polymorphism in microsatellites is an example of short tandem repeat polymorphism (STRPs), which is an important genetic marker for familial and genetic analysis.
94
What is slipped strand mispairing (SSM) or replication slippage?
This is the denaturation and displacement of DNA strands during DNA replication, resulting in the mispairing of complementary bases (also causing single nucleotide polymorphisms/SNPs, with the harmless ones being selected for. This results in genetic variation between members of the same species.)
95
What are Robertsonian translocations?
This is where two particular chromosomes join together/fuse, and is the most common form of chromosomal abnormality. Result in a reduction of the number of chromosomes. Has balanced and unbalanced forms, as seen in other chromosomal translocations.
96
What is the definition of euploidy?
This is where a cell has the correct number of chromosomes present, i.e. 46 in human cells
97
What is the definition of aneuploidy?
This is where a cell has an incorrect number of chromosomes present, i.e. 45 or 47
